This invention relates to methods for the treatment of infectious gastrointestinal disorders in humans and other animals.
Factors adversely affecting the function of the gastrointestinal system in humans are exceedingly varied in their nature. Such disorders may arise in the upper or lower gastrointestinal tracts or both. There is a broad range of causes of gastrointestinal disorders, including genetic, physiological, environmental, and psychogenic factors. Accordingly, the diagnosis and management of these is disorders can be exceptionally difficult. A detailed discussion of gastrointestinal tract functions, disorders, causes, and treatments can be found in Spiro, Clinical Gastroenterology (3d. edition 1983).
Among the chronic disorders of the upper gastrointestinal tract are those which fall under the general categories of gastritis and peptic ulcer disease. (The upper gastrointestinal tract as used herein is defined as including the esophagus, the stomach, the duodenum and the jejunum.) Gastritis is, by definition, typified by an inflammation of the stomach mucosa. In practice, though, the disorder is manifested by a broad range of poorly-defined, and heretofore inadequately treated, symptoms such as indigestion, "heart burn", dyspepsia and excessive eructation. A s general discussion of gastfitis appears in B. J. Marshall and J. R. Warren, "Unidentified Curved Bacilli in the Stomach of Patients with Gastritis and Peptic Ulceration", The Lancet, (1984), pp. 1311-1315, and in R. Greenlaw, et al., "Gastroduodenitis, A Broader Concept of Peptic Ulcer Disease", Digestive Diseases and Sciences, Vol. 25 (1980), pp. 660-672.
Peptic ulcers are lesions of the gastrointestinal tract lining, characterized by loss of tissue due to the action of digestive acids and pepsin. Historically, it was thought that peptic ulcers are caused either by gastric hypersecretion, or (more often) by decreased resistance of the gastric lining to digestive acids and pepsin.
However, since 1982, research has found an association between certain upper gastrointestinal disorders and the presence of a previously unknown organism, Helicobacter pylori (originally named "Campylobacter pylori" or "Campylobacter pyloridis." (This organism is herein referred to as "H. pylori.") See, e.g., Blaser, "Helicobacter pylori: Its Role in Disease" 15 Clinical Infectious Diseases 386 (1992); Peterson, "Helicobacter priori and Peptic Ulcer Disease" 324 New England J. of Medicine 1043 (1991); and Wyle, "Helicobacter pylori": Current Perspectives 13 J. Clinical Gastroenterology S 114 (1991).
The medical literature is replete with methods for treating ulcers, including modification of the diet, surgical removal of the lesions, and the use of drugs. Such drugs include; antacids, which serve to counteract excess gastric secretions; anticholinergics, which reduce acid secretion; H.sub.2 antagonists, which also block the release of gastric acids; prostaglandins, which increase the resistance of the gastric lining to digestive fluids, and may also inhibit acid secretion; prokinetic agents, which enhance gastrointestinal tract motility; and compositions which form protective barriers over gastric lesions. Prescription and non-prescription drug therapies are generally described in Garnet, "Antacid Products", Handbook of Non-prescription Drugs, 7th edition (1982), Chapter 3.
Regardless of the particular drug composition used in treating gastrointestinal disorders, such as gastritis or peptic ulcer disease, the treatment is often imprecise and incomplete. Actual "cures", i.e., successful treatment resulting in total remission of disease, are very often not effected. See A. J. McLean, et al., "Cyto-protective Agents and Ulcer Relapse", 142 The Medical Journal of Australia, Special Supplement S25-28 (1985). Furthermore, many conventional treatments may render subjects hypochlorhydric (i.e., with low levels of hydrochloric acid in the stomach) which may predispose them to other disorders, e.g., gastrointestinal infection, halitosis, and gastric carcinomas.
A variety of treatments have been proposed for H. priori-mediated gastrointestinal disorders. These include the use of bismuth salts (such as bismuth subsalicylate and bismuth subcitrate), and antiinfective agents (such as nitroimidazoles, fluoroquinolones, macrolides, nitrofurans, penicillins, and cephalosporins). See, e.g., European Patent Publication 206,625, Marshall, published Dec. 30, 1986; European Patent Publication 206,626 Marshall, published Dec. 30, 1986; European Patent Publication 219,912, Kraft and Morgan, published Oct. 24, 1985, European Patent Publication 282,132, Place, published Sep. 14, 1988; and European Patent Publication 455,475, Dettmar, published May 3, 1990.
However, many of these treatments afford limited success. While killing H. pylori is relatively easy in vitro, actual eradication in vivo is very difficult. Currently, single agent antimicrobial approaches designed to eradicate infection by H. pylori provide unacceptable eradication rates (i.e., &lt;80%). As a result, multiple antimicrobial agents are commonly used in combination, in particular, a triple-therapy regimen consisting of (1) a bismuth salt (e.g., bismuth subsalicylate), (2) metronidazole and (3) amoxicillin or tetracycline. The reason(s) for single agent failure and triple-therapy success remain ill defined. However, the interrelationship of multiple factors is likely to be important. Of critical significance appears to be the delivery of an appropriate antimicrobial to the gastric niche occupied by H. pylori at bactericidal concentrations for an adequate period of time. Delivery is influenced by the formulation, administration and duration of therapy. See, Borody, "Possibilities for Helicobacter pylori suppression/eradication" 4 European J. of Gastroenterology & Hepattolog S37 (1992); Glupczynski and Burette, "Drug Therapy for Helicobacter pylori Infection: Problems and Pitfalls" 85 American J. Gastroenterology 1545 (1990); Graham and Borsch, "The Who's and When's of Therapy for Helicobacter pylori" 85 American J. Gastroenterology 1552 (1990); Hentschel et al., "Antibiotic Therapy Alone Eradicates Helicobacter pylori and Prevents Duodenal Ulcer Recurrence" 105 Gastroenterology 598 (1993); Graham et al., "Effect of Triple Therapy (Antibiotics plus Bismuth) on Duodenal Ulcer Healing" 115 Annals of Internal Medicine 266 (1991); Graham et al., "Effect of Treatment of Helicobacter pylori Infection on the Long-term Recurrence of Gastric or Duodenal Ulcer" 116 Annals of Internal Medicine 705 (1992); and Graham, "Treatment of Peptic Ulcers Caused by Helicobacter pylori" 328 New England J. of Medicine 349 (1993).
It has now been discovered that H. pylori-mediated upper gastrointestinal disorders can be effectively treated with certain diphenyl ether phosphate esters. In particular, as compared to treatments among those known in the art, these methods are safe and effective to cure, or afford lower relapse rates, of gastritis and peptic ulcer disease mediated by H. pylori.